(P20-068-25) Sex-Specific Impairments in Thermogenesis and Cold Tolerance in db/db Mice: Insights Into Obesity-Associated Thermogenic Dysfunction

Objectives: Thermogenesis maintains body temperature and energy homeostasis and its dysregulation is associated with obesity. Sex differences are known to influence obesity development, but their role in obesity-related thermogenic dysfunction remains unclear. This study investigates the impairments of thermogenesis and the sex differences in cold tolerance, heat production, and thermogenic protein expression in adipose tissue of db/db mice compared to wild-type (WT) littermate controls.

Methods: The db/db and WT mice were maintained until 10 – 12 weeks old. Heat production was measured using an oxymax comprehensive lab animal monitoring system. Mice were single housed in a 4°C room for six hrs and core body temperatures were taken for the cold tolerance test. Fat pads and body weights (BW) were recorded at the sacrifice of mice. Protein expression of thermogenic protein PGC1α and UCP1 in brown and white adipose tissue (BAT and WAT) were analyzed by Western Blot.

Results: As expected, the db/db mice exhibited significantly higher body weight and produced more total heat than WT mice at room temperature. However, when normalized by body weight, heat production was lower in db/db mice than in WT mice, regardless of sex. In addition, female db/db mice demonstrated significantly lower core body temperature and poorer cold tolerance compared to either male db/db and female WT mice. Among db/db mice, female had a higher WAT/BW ratio than male db/db mice. In WT mice, while females had lower body weight and heat production than their male counterparts, no significant differences in heat production were observed after normalizing with BW. Regarding the expression of key proteins regulating thermogenesis, db/db mice showed reduced PGC1α and UCP1 protein expression than WT mice, regardless of the type of tissues or sexes.

Conclusions: The db/db mice have impaired thermogenesis, accompanied by lower thermogenic protein expression in adipose tissue in both sexes. Female db/db mice have lower core body temperatures, poorer cold tolerance and higher WAT/BW ratios than their male counterparts. These findings highlight the importance of sex differences in obesity-associated thermogenic dysfunction. The impacts of WAT/BW ratio on thermogenic regulation warrants further investigation.

Funding Sources: The study is supported by NIH grants.